This is a request to the NIH/NIDCD for a New Investigator-initiated Research Project Grant (R01) Award for Jay A. Gottfried, MD, PhD, Assistant Professor of Neurology at Northwestern University Feinberg School of Medicine. Understanding how the brain creates internal perceptions of the external world has long been a key focus of neuroscientific research. Currently little is known about the neural processing of odor objects, that is, the quality or character of a smell (e.g., minty, floral) arising from an odorous object. The long-term scientific goal of this project is to characterize the functional architecture of odor quality coding in the human brain, and to understand the roles of learning, context, and experience in the formation and modulation of these perceptual codes. The use of human subjects, who can provide direct verbal reports of their perceptual experience, offers distinct advantages for addressing these questions. In the research proposed here, olfactory functional neuroimaging techniques will be combined with sensory psychophysical approaches and computational models to characterize how (rather than simply where) neural information about odor objects is encoded in the brain. Specifically, multivariate statistical algorithms will be integrated with high-resolution imaging technologies to test the hypothesis that odor qualities and categories take the form of spatially distributed activity patterns in the human olfactory brain. The proposed studies will also pair these techniques with novel paradigms of odor sensory deprivation, olfactory perceptual illusions, and expectancy effects, to investigate whether experimentally induced changes in ensemble brain activity will coincide with parallel changes in odor quality perception. By highlighting the close affiliation between brain activity and odor object perception under dynamic conditions, these studies will demonstrate that odor-evoked ensemble patterns in human olfactory cortex satisfy criteria for a genuine olfactory code of odor quality. PUBLIC HEALTH RELEVANCE: Abnormalities in the sense of smell have particular clinical relevance for patients with Alzheimer's disease (AD), in whom deficits of smell identification and discrimination arise early in the course of illness, and often before the emergence of overt cognitive symptoms such as memory loss. Given the early accumulation of Alzheimer's pathology in olfactory limbic regions of the brain, human olfactory imaging techniques should be a highly sensitive method for assessing limbic dysfunction in this neurodegenerative disorder, opening up the possibility of developing a non-invasive imaging biomarker to predict which individuals are at risk for developing AD. Ultimately, with the emergence of novel therapeutic and preventative strategies for AD on the horizon, the need for reliable diagnostic tools, particularly for pre-symptomatic stages, will become increasingly critical, and the proposed imaging research in healthy subjects should provide important information toward this end.